T follicular helper cells (Tfh cells) are a new subset of effector cells characterized by their presence in germinal centers, the production of IL-21 and their essential role as helper of B cells and antibody (IgG) production. However, unlike other T helper subsets, a certain degree of plasticity seems to be present in Tfh cells since they are not fully committed and can lose their phenotype, and different effector cells can become Tfh cells if the right environment is present. The factor/s contributing to this plasticity remain unknown. We have shown that IL-6, a cytokine derived by a number of innate immune cells and non-hematopoietic cells, is a unique factor necessary and sufficient to induce IL-21 production in naove and memory CD4 T cells. Our preliminary studies indicate the IL-6 is also able to enhance IL-21 production during the activation of effector Th1, Th2 and Th17 cells. We have also shown that IL-6 enhances antibody responses by indirectly acting on CD4 T cells, inducing their IL-21 production, and this IL-21 acting on B cells. We propose that IL-6 is a major innate immune factor that contributes to the plasticity of Tfh cells and thereby Ab production by tonically regulating IL-21 expression in CD4 T cells without a full commitment. We also propose that the plasticity caused by IL-6 is mediated by its effect on two independent signaling pathways, 1) STAT3, modulating mitochondrial metabolism, and 2) C/EBP2, providing selective expression of IL-21. IL-6-mediated plasticity may be key in the integration of the innate immune response with CD4 and B cell responses. We will determine 1) the contribution of IL-6 to the plasticity of Tfh cells by tonically inducing IL-21 production in naive, effector and memory CD4 T cells (Aim 1), 2) the contribution of STAT3 and C/EBP2 transcription factors to the IL-6 mediated plasticity of CD4 Tfh cells (Aim 2), 3) the role of IL-6 in protective antiviral memory response by promoting memory CD4 T cells to become Tfh cells (Aim 3).